Considerable efforts are being expended to implement "Directly Observed Therapy, Short course" (DOTS) globally. However, several key assumptions about the basic biology of tuberculosis transmission, upon which this strategy is based, remain unresolved. Results obtained from our current ICIDR project and other work in which we are engaged have lead us to hypothesize that, in the context of a well functioning DOTS based program, 1) relying solely on sputum microscopy (AFB smear) for diagnosis provides a biased underestimate of TB epidemiology, 2) that patients who are AFB smear negative, but culture positive (termed "paucibacillary") contribute significantly to disease transmission 3) that there are concerning rates of ongoing transmission of drug resistant M. tuberculosis, and 4) insight gained from the availability of the complete genomic sequence of M. tuberculosis can be exploited to provide clinically and epidemiologically relevant understanding of M. tuberculosis population genetics. We now propose to use "state of the art" molecular epidemiologic techniques to test these hypotheses. These results will have immediate implications for tuberculosis control programs in many tropical countries. In addition, the availability of fully characterized strains from this study will allow us to examine the nature and consequence of genetic diversity within populations of M. tuberculosis and begin to exploit this information for improved genotyping and diagnostic systems.